Non-Alcoholic Fatty Liver Disease (NAFLD)
Nutritional and Supplemental Support
In contrast to the failure of most pharmacological therapies, numerous nutritional approaches show real promise in slowing the development and progression of NAFLD. In particular, Life Extension has identified seven integrative interventions with scientifically validated effectiveness.
Scientists began a series of studies on NASH (the advanced middle stage of NAFLD) and vitamin E in 2004. Based on their knowledge that NASH arises from persistent insulin resistance and oxidative stress, they examined the effects of pioglitazone (Actos), an insulin-sensitizing drug, and vitamin E. Patients receiving both vitamin E (400 IU per day) and pioglitazone (30 mg per day) had improvements in more parameters than did patients on vitamin E alone.31
In a follow-up study, subjects received either vitamin E (800 IU per day) or pioglitazone (30 mg per day), or placebo, for 96 weeks.
Both treatments improved levels of liver cell-injury markers in blood, and both reduced liver fat levels and inflammation. But only vitamin E produced significant improvements in the appearance of liver tissue on biopsies.32 Here are some clues that explain these otherwise startling results.
Vitamin E is a powerful antioxidant, and an obvious choice once the role of oxidant stress was made clear in NAFLD.33 People with fatty liver disease and NASH have depressed levels of vitamin E in their blood, the result of increased oxidation.34,35 Even relatively low-dose vitamin E (450 IU/day) can reduce circulating liver enzymes, a chemical marker of liver cell injury.36,37
Important animal studies refine our understanding of how vitamin E works. One study provided the first evidence that vitamin E can prevent NAFLD before it develops, largely by reducing oxidative stress, inflammation, and liver cell death by apoptosis.38 Another study demonstrated a vitamin E-related reduction in oxidative damage and tissue levels of the inflammatory mediator tumor necrosis factor-alpha (TNF-α), while beneficially reducing PPAR-gamma activity.39 This wealth of animal and now human data clearly supports daily use of 800‒1,200 IU of vitamin E for prevention and treatment of NAFLD and NASH.
Omega-3 Fatty Acids
Just as vitamin E fights the oxidant and inflammatory components of NAFLD, the omega-3 fatty acids attack the problem of lipotoxicity, while contributing considerable anti-inflammatory activity of their own.12 People and experimental animals with insufficient omega-3 in their diets are prone to NAFLD and type 2 diabetes, suggesting that supplementation might reverse (or prevent) the process.12,40-42
Increasing the amount of unsaturated fats like omega-3s in cell membranes is associated with improved insulin sensitivity.43 And supplementation with omega-3 rich fish oil results in activation of the important metabolic sensor, called PPAR-alpha, in liver cells, suppressing production of new fat molecules.44 Omega-3s also contribute to improved insulin sensitivity, a reduction in serum triglycerides, and stimulation of fat utilization in liver tissue and skeletal muscle.45
A long-term human trial, using 1,000 mg per day of omega-3, revealed significant decreases in serum markers of liver cell damage, triglyceride levels, and fasting glucose. Most impressively, supplemented patients display improvement of their livers’ appearance and blood flow on ultrasound exams, providing graphic evidence of the supplements’ benefits.46 Another study found that supplementation with 751 mg eicosapentaenoic acid (EPA) and 527 mg docosahexaenoic acid (DHA) three times daily for 24 weeks decreased triglyceride levels in individuals with NAFLD.47 Olive oil also decreases accumulation of triglycerides in the liver during NAFLD, but fish oil provided better antioxidant activity.48 Olive oil also independently improves postprandial triglyceride levels in blood and upregulates glucose transporter in liver. At the same time, it improves insulin resistance by decreasing liver inflammation.49 And long-term consumption of olive oil enriched with omega-3 fats in patients with NAFLD is able to improve liver texture on ultrasound exams, while improving serum markers of liver injury and increasing protective adiponectin levels.50
Clearly the omega-3 fatty acids have earned their designation as an innovative therapy for NAFLD.51
Their constant exposure to oxidant and toxic stresses makes liver cells especially vulnerable to depletion of glutathione (GSH), a natural antioxidant that participates in many liver detoxification reactions.52,53 The nutrient S-adenosylmethionine (SAMe) can replenish GSH levels and restore liver cell protection to normal.54 In individuals with alcoholic or non-alcoholic liver disease, supplementation with 1,200 mg SAMe daily increased liver glutathione levels.55 Studies using agents that increase SAMe levels are known to reduce severity of NAFLD.52,56
SAMe and other liver antioxidants improve levels of liver enzymes, an early marker of cell damage.57 SAMe supplements improve microscopic features of NAFLD associated with fatty degeneration, inflammation, and tissue death. And SAMe also down-regulated damaging proinflammatory genes in an animal model of NAFLD.54
A major discovery about SAMe is that it directly stops progression of relatively mild NAFLD to dangerous NASH. NASH develops as the result of “second hits,” that is, additional events that damage liver cells after NAFLD has already developed; one of those “hits” is steady depletion of SAMe.58 This has led to interest in using SAMe to prevent NASH from developing in people who already have NAFLD.59
Another molecule that supports and replenishes the natural antioxidant glutathione is N-acetyl cysteine (NAC), a versatile sulfur-rich compound that prevents liver damage following acetaminophen poisoning.60 It rapidly restores depleted glutathione levels, sparing liver cells from the effects of oxidant damage.61-63
A NAC derivative, called SNAC, was recently shown to prevent onset of NAFLD in rats fed a liver disease-inducing diet.64 In humans, the combination of NAC (1,200 mg/day) with metformin (850‒1,000 mg/day) improved liver appearance and reduced fibrosis in patients with NAFLD.29 And, given to rats with NAFLD, NAC stimulates regeneration of healthy liver cells in animals that have part of their livers removed.65
Silymarin (Milk Thistle)
Extracts of milk thistle have long been used for liver protection. Silymarin is composed of six major active molecules such as silybin, which are known as flavonolignans, having exceptional antioxidant and anti-inflammatory activity.66,67
One very effective combination is silymarin plus vitamin E and phospholipids (such as phosphatidylcholine); this approach improves the overall antioxidant activity of the compound.68 In animal studies the combination limited liver depletion of the natural antioxidant glutathione, and reduced mitochondrial stress damage.69 Human trials have shown that a preparation providing 376 mg silybin, 776 mg phosphatidylcholine, and 360 mg vitamin E produces therapeutic effects in patients with a variety of different forms of liver damage, improving insulin resistance, reducing liver fat accumulation, and reducing blood levels of markers of liver scarring.70,71
Phosphatidylcholine and Polyenylphosphatidylcholine (PPC)
Phospholipids—fat molecules with phosphate groups attached—are major constituents of cell membranes in mammals. One of the most important phospholipids in humans is phosphatidylcholine. Higher amounts of phosphatidylcholine in cell membranes help to assure membrane integrity in the face of oxidative and other stresses; they also help limit the progression of NAFLD into NASH.72
A particularly rich source of phosphatidylcholine molecules is a mixture called polyenylphosphatidylcholine (PPC), derived from soybeans.73 PPC supplements in animals attenuate non-alcoholic liver fibrosis and even accelerate its regression.74 PPC appears to exert this effect in part by blocking oxidant damage to cell membranes.75-77 A separate mechanism is reduction in the high cholesterol levels that precede NAFLD formation.78 PPC also prevents proliferation of scar tissue in NAFLD and other forms of liver toxicity.79 And PPC restores liver cell levels of SAMe, providing additional liver protection.80
Resveratrol protects liver tissue against the ravages of alcoholic fatty liver disease through its antioxidant effects, buffering the impact of alcohol.81 It also activates two critical signaling molecules, SIRT1 and AMPK, which are inhibited by alcohol, and are also dysfunctional in metabolic syndrome.82-85 Those effects make it highly promising for prevention of NAFLD, the liver manifestation of metabolic syndrome. In animal studies, resveratrol activates AMPK, which in turn reduces liver fat accumulation, suppresses new liver fat formation, and reduces insulin resistance.86-88
Note: NAFLD and NASH are progressive conditions that require patient collaboration with a qualified physician. Because the liver metabolizes many nutrients and drugs, it is important that liver patients not add any substances to their regimen without cooperation and close monitoring by a qualified physician. The goals of therapy are:
- Reduce the accumulation of fat in liver tissue by decreasing new fat synthesis and increasing utilization of existing fat stores in the liver.
- Minimize free radical production, and enhance free radical scavenging in liver tissue
- Reduce or eliminate the inflammatory responses of fat-infiltrated liver tissue to prevent progression of NAFLD to the more-deadly NASH, which is a precursor of liver failure.
Disclaimer and Safety Information
This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the treatments discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.
The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. The publisher has not performed independent verification of the data contained herein, and expressly disclaim responsibility for any error in literature.